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The Journal of Neuroscience, March 15, 2001, 21(6):1819-1829

Chronic Exposure to Nicotine Upregulates the Human 42 Nicotinic Acetylcholine Receptor Function

Bruno Buisson and Daniel Bertrand

Department of Physiology, Medical Faculty, 1211 Geneva 4, Switzerland

Widely expressed in the brain, the 42 nicotinic acetylcholine receptor (nAChR) is proposed to play a major role in the mechanisms that lead to and maintain nicotine addiction. Using the patch-clamp technique and pharmacological protocols, we examined the consequences of long-term exposure to 0.1-10 µM nicotine in K-177 cells expressing the major human brain 42 receptor. The acetylcholine dose-response curves are biphasic and revealed both a high- and a low-affinity component with apparent EC₅₀ values of 1.6 and 62 µM. Ratios of receptors in the high- and low-affinity components are 25 and 75%, respectively. Chronic exposure to nicotine or nicotinic antagonists [dihydro--erytroidine (DHE) or methyllycaconitine (MLA)] increases the fraction of high-affinity receptors up to 70%. Upregulated acetylcholine-evoked currents increase by twofold or more and are less sensitive to desensitization. Functional upregulation is independent of protein synthesis as shown by the lack of effect of 20 µM cycloheximide. Single-channel currents recorded with 100 nM acetylcholine show predominantly high conductances (38.8 and 43.4 pS), whereas additional smaller conductances (16.7 and 23.5 pS) were observed with 30 µM acetylcholine. In addition, long-term exposure to dihydro--erytroidine increases up to three times the frequency of channel openings. These data indicate, in contrast to previous studies, that human 42 nAChRs are functionally upregulated by chronic nicotine exposure.

Key words: acetylcholine; nicotinic receptor; 42; nicotine; upregulation; nicotine addiction

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2161819-11$05.00/0

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